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The role of Notch signaling in tumor angiogenesis and blood vessel maturation

Elizabeth Lea Scheppke Smoot

Appointment Period: 2010-2011, Grant Years: [26]

Elizabeth Lea Scheppke SmootThe vasculature of solid tumors is characterized by a network of blood vessels that are tortuous, disorganized, and leaky, with a paucity of perivascular cells. This leads to poor perfusion, edema and ischemia within the tumor bed, and hinders systemic delivery of chemotherapeutics to the area. The only signaling pathway known to be involved in nearly all aspects of blood vessel development, from initial vessel formation and patterning to vessel maturation and specialization, is the Notch receptor/ligand family. Additionally, Notch receptor/ligand expression is deregulated in a number of solid tumors, including cervical, renal, lung, and breast, which potentially impacts the development and maturation of newly recruited tumor blood vessels.

The goal of this project was to understand the Notch downstream effectors that regulate the recruitment of vascular smooth muscle cells to newly formed arteries, resulting in a stable and mature arterial vasculature. I found that Notch signaling in vascular smooth muscle cells leads to the upregulation of integrin alpha v beta 3, which is known to be important in cell adhesion and migration. I also discovered that vascular smooth muscle cells use this integrin to adhere to the extracellular matrix protein von Willebrand Factor, which is deposited specifically in the endothelial basement membrane. Importantly, the endothelial basement membranes of tumor vessels are abnormal in their extracellular matrix composition, and many lack von Willebrand Factor accumulation. These findings could explain the relative lack of vascular smooth muscle cells within tumors, and the instability of those vessels, since the recruitment of perivascular cells is known to stabilize nascent vessels.

Scheppke L, Murphy EA, Zarpellon A, Hofmann JJ, Merkulova A, Shields DJ, Weis SM, Byzova TV, Ruggeri ZM, Iruela-Arispe ML, Cheresh DA. Notch promotes vascular maturation by inducing integrin-mediated smooth muscle cell adhesion to theendothelial basement membrane. Blood. 2012 Mar 1;119(9):2149-58. Epub 2011 Dec 1.PubMed PMID: 22134168; PubMed Central PMCID: PMC3311249.